CZ19997A3 - Semisynthetic taxanes, process of their preparation pharmaceutical composition containing thereof and intermediates for their preparation - Google Patents
Semisynthetic taxanes, process of their preparation pharmaceutical composition containing thereof and intermediates for their preparation Download PDFInfo
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- CZ19997A3 CZ19997A3 CZ97199A CZ19997A CZ19997A3 CZ 19997 A3 CZ19997 A3 CZ 19997A3 CZ 97199 A CZ97199 A CZ 97199A CZ 19997 A CZ19997 A CZ 19997A CZ 19997 A3 CZ19997 A3 CZ 19997A3
- Authority
- CZ
- Czechia
- Prior art keywords
- hydroxy
- phenyl
- formula
- acyloxy
- taxanes
- Prior art date
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- 229940123237 Taxane Drugs 0.000 title claims description 25
- 238000000034 method Methods 0.000 title claims description 9
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 5
- 238000002360 preparation method Methods 0.000 title description 14
- 239000000543 intermediate Substances 0.000 title description 3
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical group NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims abstract description 10
- 230000032050 esterification Effects 0.000 claims abstract description 6
- 238000005886 esterification reaction Methods 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims description 19
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 18
- 125000004423 acyloxy group Chemical group 0.000 claims description 16
- -1 2,2,2-trichloroethoxycarbonyloxy Chemical group 0.000 claims description 10
- DKPFODGZWDEEBT-QFIAKTPHSA-N taxane Chemical class C([C@]1(C)CCC[C@@H](C)[C@H]1C1)C[C@H]2[C@H](C)CC[C@@H]1C2(C)C DKPFODGZWDEEBT-QFIAKTPHSA-N 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 5
- 125000006239 protecting group Chemical group 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 125000001072 heteroaryl group Chemical group 0.000 claims description 4
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 4
- 125000004648 C2-C8 alkenyl group Chemical group 0.000 claims description 3
- 230000009897 systematic effect Effects 0.000 claims 4
- 125000002252 acyl group Chemical group 0.000 claims 2
- 125000003837 (C1-C20) alkyl group Chemical group 0.000 claims 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims 1
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 claims 1
- YWLXLRUDGLRYDR-ZHPRIASZSA-N 5beta,20-epoxy-1,7beta,10beta,13alpha-tetrahydroxy-9-oxotax-11-ene-2alpha,4alpha-diyl 4-acetate 2-benzoate Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](O)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 YWLXLRUDGLRYDR-ZHPRIASZSA-N 0.000 abstract description 16
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical class O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 abstract description 16
- 230000000259 anti-tumor effect Effects 0.000 abstract description 8
- 230000001472 cytotoxic effect Effects 0.000 abstract description 5
- 231100000433 cytotoxic Toxicity 0.000 abstract description 4
- 230000003647 oxidation Effects 0.000 abstract description 4
- 238000007254 oxidation reaction Methods 0.000 abstract description 4
- 230000000707 stereoselective effect Effects 0.000 abstract description 3
- 238000002347 injection Methods 0.000 abstract description 2
- 239000007924 injection Substances 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 72
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 48
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 36
- 239000000243 solution Substances 0.000 description 21
- 239000000047 product Substances 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 229930012538 Paclitaxel Natural products 0.000 description 14
- 229960001592 paclitaxel Drugs 0.000 description 13
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
- DCFKHNIGBAHNSS-UHFFFAOYSA-N chloro(triethyl)silane Chemical compound CC[Si](Cl)(CC)CC DCFKHNIGBAHNSS-UHFFFAOYSA-N 0.000 description 10
- 239000000203 mixture Substances 0.000 description 10
- 239000011541 reaction mixture Substances 0.000 description 10
- 239000000741 silica gel Substances 0.000 description 9
- 229910002027 silica gel Inorganic materials 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 7
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 5
- 210000004027 cell Anatomy 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 238000005828 desilylation reaction Methods 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- LJCZNYWLQZZIOS-UHFFFAOYSA-N 2,2,2-trichlorethoxycarbonyl chloride Chemical compound ClC(=O)OCC(Cl)(Cl)Cl LJCZNYWLQZZIOS-UHFFFAOYSA-N 0.000 description 2
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- OVMSOCFBDVBLFW-VHLOTGQHSA-N 5beta,20-epoxy-1,7beta,13alpha-trihydroxy-9-oxotax-11-ene-2alpha,4alpha,10beta-triyl 4,10-diacetate 2-benzoate Chemical compound O([C@@H]1[C@@]2(C[C@H](O)C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)O)C(=O)C1=CC=CC=C1 OVMSOCFBDVBLFW-VHLOTGQHSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 2
- 239000007995 HEPES buffer Substances 0.000 description 2
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 2
- 229930182816 L-glutamine Natural products 0.000 description 2
- 241001529936 Murinae Species 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 125000003342 alkenyl group Chemical group 0.000 description 2
- 210000000481 breast Anatomy 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical group [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 210000000936 intestine Anatomy 0.000 description 2
- 208000032839 leukemia Diseases 0.000 description 2
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 2
- 210000001672 ovary Anatomy 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 description 1
- 150000000703 Cerium Chemical class 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 229910000831 Steel Inorganic materials 0.000 description 1
- 241001116500 Taxus Species 0.000 description 1
- 241001116498 Taxus baccata Species 0.000 description 1
- 235000009065 Taxus cuspidata Nutrition 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 229940009456 adriamycin Drugs 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 238000011717 athymic nude mouse Methods 0.000 description 1
- 229930014667 baccatin III Natural products 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000003130 cardiopathic effect Effects 0.000 description 1
- 230000001451 cardiotoxic effect Effects 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- 229940076286 cupric acetate Drugs 0.000 description 1
- 125000005594 diketone group Chemical group 0.000 description 1
- 229930004069 diterpene Natural products 0.000 description 1
- 125000000567 diterpene group Chemical group 0.000 description 1
- ODCCJTMPMUFERV-UHFFFAOYSA-N ditert-butyl carbonate Chemical compound CC(C)(C)OC(=O)OC(C)(C)C ODCCJTMPMUFERV-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- LULAYUGMBFYYEX-UHFFFAOYSA-N metachloroperbenzoic acid Natural products OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 description 1
- 229940042880 natural phospholipid Drugs 0.000 description 1
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 description 1
- 239000008389 polyethoxylated castor oil Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- SCPYDCQAZCOKTP-UHFFFAOYSA-N silanol Chemical compound [SiH3]O SCPYDCQAZCOKTP-UHFFFAOYSA-N 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000010959 steel Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 150000004579 taxol derivatives Chemical class 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
- C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Epoxy Compounds (AREA)
Abstract
Description
(54) Název přihlášky vynálezu:(54) Title of the invention:
Semisynthetické taxany, způsob jejich výroby, farmaceutické prostředky s jejich obsahem a meziprodukty pro jejich výrobu (57) Anotace:Semisynthetic taxanes, process for their preparation, pharmaceutical compositions containing them and intermediates for their production (57)
Nové deriváty získané oxidací a stereospecifickou redukcí 10-deacetylbaccatinu III, po nichž následuje esteriflkace různě substituovaným ísoserinovým řetězcem k přípravě taxolových analogů, produkty podle vynálezu mají cytotoxické a protinádorové účinky a pokud jsou vhodně upraveny, mohou být podávány injekčně nebo perorálně.Novel derivatives obtained by oxidation and stereospecific reduction of 10-deacetylbaccatin III, followed by esterification of differently substituted isoserine chains to prepare taxol analogs, the products of the invention have cytotoxic and antitumor effects and, if appropriately modified, can be administered by injection or orally.
CZ 199-97 A3CZ 199-97 A3
- 1 •nad _ ' - I- 1 • over _ '- I
JAiD l~N ÍS VIA !JAiD l ~ Ns us!
OHlAOlSAlAIOad ’ . avy o ' f OHlAOlSAlAIOad '. avy o ' f
Polosynthetické taxany, způsob jejich výroby, farmac^igti^lpi t 1 prostředky s jejich obsahem a meziprodukty pro jejich výrobu.Semisynthetic taxanes, process for their production Farmaco igti ^ ^ t 1 lpi compositions containing them and intermediates for their production.
( OISOO ( OISOO
Oblast techniky 0 i U Ž 0 ! T'o j · Λ ITechnical field 0 i U 0! T'o j · Λ I
Vynález se týká nových derivátů, získaných oxtdeet—a--»— stereospecifickou redukcí 10-deacetylbaccatinu III a následnou esterifikací různě substituovaným řetězcem isoserinu k přípravě taxolových analogů. Látky podle vynálezu mají cytotoxický a protinádorový účinek.The invention relates to novel derivatives obtained by oxtdeet- and - »- by stereospecific reduction of 10-deacetylbaccatin III and subsequent esterification with a differently substituted isoserine chain to prepare taxol analogs. The compounds of the invention have a cytotoxic and antitumor effect.
Dosavadní stav technikyBACKGROUND OF THE INVENTION
O diterpenech se strukturou taxanů, a zejména taxolu, je známo, že vykazují protinádorové působení vůči mnoha lidským nádorům. Ovšem použití těchto léků (drog) a zvláště taxolu má i některé nevýhody, a to nežádoucí vedlejší účinky. Z tohoto důvodu, a také vzhledem k rychlému indukování odolnosti při podobné protinádorové léčbě, je žádoucí vyvinutí nových molekul, které by zmírnily obtíže, pozorované při klinickém použití.Diterpenes with a taxane structure, and in particular taxol, are known to have antitumor activity against many human tumors. However, the use of these drugs and especially taxol also has some disadvantages, namely undesirable side effects. For this reason, and also due to the rapid induction of resistance in similar antitumor therapy, it is desirable to develop new molecules that would alleviate the difficulties observed in clinical use.
WO 93/02067 (Nippon Steel) ze 4. 2. 1993 předkládá například 10-alfa-acetyltaxol, extrahovaný z tkáňové kultury bílkoviny rodu Taxus, mající výraznou cytotoxickou aktivitu.WO 93/02067 (Nippon Steel) of February 4, 1993 discloses, for example, 10-alpha-acetyltaxol, extracted from a tissue culture of a protein of the genus Taxus, having significant cytotoxic activity.
Podstata vynálezuSUMMARY OF THE INVENTION
Předkládaný vynález se týká nových derivátů s taxanovou kostrou, získaných polosyntheticky a vykazujících silný protinádorový účinek.The present invention relates to novel taxane backbone derivatives, obtained semisynthetically and showing potent antitumor activity.
Deriváty podle vynálezu mají vzorec (1):The derivatives of the invention have the formula (1):
Mohou být rozděleny do dvou skupin:They can be divided into two groups:
a) Taxanové deriváty, obsahující dvojitou olefinovou vazbu v polohách 11,12 a hydroxy- nebo acyloxyskupinu v poloze 10a (taxany o vzorci 1a)(a) Taxane derivatives containing a double olefinic bond at positions 11,12 and a hydroxy- or acyloxy group at position 10a (taxanes of formula 1a)
b) taxanové deriváty, obsahující jednoduchou vazbu mezi uhlíkovými atomy v poloze 11a 12, methylovou skupinu v poloze 12 v orientaci a, a hydroxy- či acyloxyskupinu v poloze β (taxany o vzorci 1b)(b) taxane derivatives containing a single bond between the carbon atoms at positions 11 and 12, a methyl group at the 12 position in the a position, and a hydroxy or acyloxy group at the β position (taxanes of formula 1b)
U taxanú obecného vzorce (1) jsou R1 a R2, buď stejné nebo odlišné, C^Cg alkylovou, C2-C8 alkenylovou, arylovou (s výhodou fenylovou) nebo heteroarylovou skupinou. R2 může být také terciární butoxyskupinou.In the taxanes of formula (1), R 1 and R 2 are either the same or different, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, aryl (preferably phenyl) or heteroaryl. R 2 may also be a tertiary butoxy group.
U sloučenin o vzorci (1a) R3 je vodík a R4 je hydroxylová skupina nebo C2-C8 acyloxyskupina.For compounds of formula (1a), R 3 is hydrogen and R 4 is hydroxyl or C 2 -C 8 acyloxy.
U sloučenin o vzorci (1b) je R3 hydroxylová skupina nebo C2-C8 acyloxyskupina a R4 je vodík.For compounds of formula (1b), R 3 is hydroxy or C 2 -C 8 acyloxy and R 4 is hydrogen.
Taxany o vzorci (1) jsou vyráběny esterifikací polohy 13 nových syntonú o vzorci (2), za použití vhodně aktivovaných isoserinových řetězců jako acylačních činidel, a to podle popisu v literatuře pro polosynthesu taxolú a jejich analogů (viz např. EP-A-400971, 1992, Fr. Dem. 86, 10400; E. Didier se spol., Tetrahedron Letters 35, 2349, 1994, E. Didier se spol., Tetrahedron Letters 35, 3063, 1994).Taxanes of formula (1) are produced by esterifying position 13 of the new syntones of formula (2), using appropriately activated isoserine chains as acylating agents, as described in the literature for the semi-synthesis of taxols and analogues thereof (see, eg, EP-A-400971 86: 10400, E. Didier et al., Tetrahedron Letters 35, 2349 (1994), E. Didier et al., Tetrahedron Letters 35, 3063, 1994).
- 4 5- 4 5
Ve vzorci (2)In formula (2)
RR
(2) platí:(2) the following applies:
pokud je přítomna dvojná olefinová vazba v poloze 11,12, je R3 vodíkový atom a R4 a Rs jsou hydroxylové skupiny, C2-C„ acyloxyskupiny, alkylsiiyloxyskupiny nebo 2,2,2-trichlorethoxykarbonyloxyskupiny; a pokud není přítomna dvojná olefinová vazba v poloze 11,12, má methyl v poloze 12 orientaci a, R4 je atom vodíku a R3 a R4 jsou hydroxylové skupiny, C2-C8 acyloxyskupiny, alkylsiiyloxyskupiny nebo 2,2,2-trichlorethoxykarbonyloxyskupiny.when a double olefinic bond is present in position 11,12, R 3 is hydrogen and R 4 and R are hydroxy, C 2 -C "acyloxy alkylsiiyloxyskupiny or 2,2,2-trichloroethoxycarbonyloxy groups; and in the absence of a double olefinic bond at the 11,12 position, the methyl at the 12-position has the orientation a, R 4 is a hydrogen atom, and R 3 and R 4 are hydroxyl, C 2 -C 8 acyloxy, alkylsilyloxy or 2,2,2 -trichloroethoxycarbonyloxy.
Konkrétně syntony o vzorci 2a jsou používány pro synthesu nových taxanú o vzorci (1a). Na druhou stranu, syntony o vzorci (2b) jsou používány pro synthesu nových taxanú o vzorci (1b).In particular, the syntones of formula 2a are used to synthesize new taxanes of formula (1a). On the other hand, the syntons of formula (2b) are used for the synthesis of new taxanes of formula (1b).
•5• 5
O (2a)O (2a)
- 5 U syntonů (2a) je dvojná olefinová vazba přítomna v poloze 11, 12 a C2-C8 acyloxyskupina anebo volitelně chráněná hydroxyskupina jsou přítomné v poloze 10a. U syntonů (2a) je tedy R3 vodík a R4 a Rs jsou hydroxyskupiny, acyloxyskupiny, alkylsilyloxyskupiny Qako triethylsilyloxyskupina, O-TES) nebo 2,2,2-trichlorethoxykarbonyloxyskupiny (O-CO-O-CH2CCI3, O-TROC) .For the syntones (2a), the double olefinic bond is present at the 11, 12 and C 2 -C 8 acyloxy groups or the optionally protected hydroxy group is present at the 10a position. In syntones (2a), thus R 3 is hydrogen and R 4 and R are hydroxy, acyloxy, alkylsilyloxy Qako triethylsilyloxy, O-TES) or 2,2,2-trichloroethoxycarbonyloxy (O-CO-O-CH 2 CCl 3, O -TROC).
U syntonů (2b) jsou uhlíkové atomy v polohách 11 a 12 vázány jednoduchou vazbou, methyl v poloze 12 má orientaci a, a acyloxyskupina nebo volitelně chráněná hydroxyskupina jsou přítomné v poloze 10a. U syntonů (2b) je tedy R4 vodík a R3_ a Rs jsou hydroxyskupiny, acyloxyskupiny, alkylsilyloxyskupiny (jako triethylsilyloxyskupina, O-TES) nebo 2,2,2-trichlorethoxykarbonyloxyskupiny (O-CO-O-CH2CCI3, O-TROC) .For the syntones (2b), the carbon atoms at positions 11 and 12 are bonded by a single bond, the methyl at position 12 is in the α, and the acyloxy or optionally protected hydroxy group is present at the 10a position. In syntones (2b), i.e., R 4 is hydrogen and R 3 _ and R are hydroxy, acyloxy, alkylsilyloxy (such as triethylsilyloxy, O-TES) or 2,2,2-trichloroethoxycarbonyloxy (O-CO-O-CH 2 CCl 3 , O-TROC).
Po esterífikaci syntonů (2) v poloze 13 ísoserinovým řetězcem jsou k získání nových taxanú o vzorci (1) chránící skupiny odstraněny běžnými metodami, známými z literatury.After esterification of the syntons (2) at position 13 with the isoserine chain, the protecting groups are removed by conventional methods known in the literature to obtain new taxanes of formula (1).
- 6 10-deacetylbaccatin III (3), který lze isolovat z listů Taxus Baccata (G. Chauviěre se spol., C.R. Acad. Sc. Ser. III, 293, 591, 1981), je používán jako výhradní výchozí produkt pro výrobu syntonů (2a) a (2b).- 6 10-Deacetylbaccatin III (3), which can be isolated from leaves of Taxus Baccata (G. Chauviere et al., CR Acad. Sc. Ser. III, 293, 591, 1981), is used as the sole starting product for the production of syntons (2a) and (2b).
Syntony o vzorci (2a), které nejsou z literatury známé, jsou získávány (viz Schéma 1) z látky (3) oxidací octanem měďnatým v poloze 10 za vzniku diketonu o vzorci (4) a následnou redukcí borohydridem sodným v přítomnosti ceritých solí.Syntones of formula (2a), which are not known in the literature, are obtained (see Scheme 1) from (3) by oxidation with cupric acetate at position 10 to give a diketone of formula (4) and subsequent reduction with sodium borohydride in the presence of cerium salts.
Výsledný produkt (2a, R3 = H, R4 = Rs = OH), který je epimerem v poloze 10 látky (3), je vhodně chráněn v polohách 7 a 10 a použit k synthese taxanů (1a).The resulting product (2a, R3 = H, R 4 = R s = OH), which is the epimer at the 10- position of compound (3) is suitably protected in positions 7 and 10, and used for the synthesis of taxanes (1a).
Cu(OAc)2 Cu (OAc) 2
Jako vedlejší produkt reakčního kroku, znázorněného na schématu 1, je získán nový sekotaxan (5)As a by-product of the reaction step shown in Scheme 1, a new secotaxane (5) is obtained.
(5)(5)
- 8 Sekotaxan (5) může být použit pro synthesu dalších taxanú s možnou protinádorovou aktivitou.Sekotaxane (5) can be used to synthesize other taxanes with possible antitumor activity.
Předkládaný vynález se rovněž týká nových derivátů se sekotaxanovou kostrou, připravovaných polosyntheticky a majících silnou protinádorovou aktivitu. Takové deriváty mají vzorec (5a)The present invention also relates to novel secotaxane backbone derivatives prepared semi-synthetically and having potent antitumor activity. Such derivatives have the formula (5a)
kde:where:
R1 a Rj, stejné nebo odlišné, jsou C,-C20 alkylové, C2-Ca alkenylové, arylové (s výhodou fenylové) nebo heteroarylové skupiny. R2 může být také terciární butoxyskupina.R 1 and R 1, the same or different, are C 1 -C 20 alkyl, C 2 -C and alkenyl, aryl (preferably phenyl) or heteroaryl groups. R 2 may also be a tertiary butoxy.
Taxany o vzorci (5a) jsou připravovány esterifikací sloučeniny (5) v poloze 13, za použití vhodně aktivovaných isoserinových řetězců jako acylačních činidel, jak je popsáno v literatuře, zabývající se polosynthesou taxolu a jeho analogů (viz např. EP-A-400971; E. Didier se spol., Tetrahedron Letters 35, 2349, 1994; E. Didier se spol., Tetrahedron Letters 35, 3063, 1994). Hydroxyskupiny sloučeniny (5) mohou být volitelně chráněny vhodnými chránícími skupinami podle běžných metod.The taxanes of formula (5a) are prepared by esterifying compound (5) at position 13, using appropriately activated isoserine chains as acylating agents, as described in the literature dealing with the polysynthesis of taxol and analogs thereof (see, eg, EP-A-400971; E. Didier et al., Tetrahedron Letters 35, 2349, 1994; E. Didier et al., Tetrahedron Letters 35, 3063, 1994). The hydroxy groups of compound (5) may optionally be protected by suitable protecting groups according to conventional methods.
Po esterifikaci sloučeniny (5) v poloze 13 isoserinovým řetězcem jsou k získání sekotaxanů o vzorci (5a) chránící skupiny odstraněny obvyklými postupy, známými z literatury.After esterification of compound (5) at position 13 with the isoserine chain, the protecting groups are removed by conventional methods known in the literature to obtain the secotaxanes of formula (5a).
Syntony o vzorci (2b) , které nejsou z literatury známé, se rovněž získávají z 10-deacetylbaccatinu III (3), viz schéma 2. Bylo zjištěno, že oxidací látky (3) kyselinou m-chloroperbenzoovou (MCPBA) se získá odpovídající 13-ketoderivát (6). Po ochraně hydroxylu v poloze 7 triethylsilylchloridem (TESCI) poskytuje látka (6) při redukci borohydridem sodným v přítomnosti ceritých solí synton (2b) (R3 = OH, R4 = H, Rs = O-TES), který může být výhodný pro synthesu taxanu o vzorci (1b). Orientace a methylu v poloze 12 u syntonů (2b) byla vyvozena na základě důkladných studií za použití nukleární magnetické resonance.Syntones of formula (2b), which are not known in the literature, are also obtained from 10-deacetylbaccatin III (3), see Scheme 2. It has been found that oxidation of (3) with m-chloroperbenzoic acid (MCPBA) yields the corresponding 13- ketoderivative (6). After protection of the hydroxyl at the 7-position with triethylsilyl chloride (TESCI), compound (6) in the reduction with sodium borohydride provides syntones (2b) (R 3 = OH, R 4 = H, R s = O-TES) which may be preferred for the synthesis of a taxane of formula (1b). Orientation and methyl at the 12-position of the syntons (2b) were based on thorough studies using nuclear magnetic resonance.
- 10 Schéma 2- 10 Scheme 2
MCPBAMCPBA
.........— ->.........— ->
1. TESCI1. TESCI
2. NaBH /CeCl,2. NaBH / CeCl
33
OO
OH 0 Ph-/ *cQr'OH 0 Ph- / * cQr '
2b (R =QH, R = 3 42b (R = QH, R = 344)
H, R5=O'TESH, R5 = O'TES
- 11 Produkty podle tohoto vynálezu byly testovány vzhledem k jejich cytotoxickému působení na různé nádorové buněčné linie a jejich účinek byl srovnáván s taxolem. Tabulka 1 ukazuje hodnoty ICS0, ve srovnání se stejným údajem pro taxol, sloučenin 13-[(2R, 3S)-3-fenyl-2-hydroxy-3-ř-butoxykarbonylaminopropanoyl]-10-epi-10-deacetylbaccatinu III (1a, R1 = Ph, R2 = tBuO, R3 = H, R4 = OH), 13-[(2R, 3S)-3-fenyi-2-hydroxy-3-ř-butoxykarbonylaminopropanoyl]-10-deacetyl-11,12-dihydrobaccatinu III (1b, R, = Ph, R2= tBuO, R3 = OH, R4 = H), 13-[(2R, 3S)-3-fenyl-2-hydroxy-3-f-butoxykarbonylaminopropanoyl] -C-seko-10-deacetylbaccatinu III (5a, R, = Ph, R2 = tBuO) a 13-[(2R, 3S)-3-isobutyl-2-hydroxy-3-kaproylaminopropanoyl]-C-seko-10-deacetylbaccatinu (5a, R1 =isobutyl, R2 = pentyl).The products of this invention were tested for their cytotoxic effect on various tumor cell lines and their effect was compared to taxol. Table 1 shows the IC S0, compared with the same parameter for taxol, of the compounds 13 - [(2R, 3S) -3-phenyl-2-hydroxy-3-t-butoxycarbonylamino-propanoyl] -10-epi-10-deacetylbaccatine III (1a, R 1 = Ph, R 2 = tBuO, R 3 = H, R 4 = OH), 13 - [(2 R, 3 S) -3-phenyl-2-hydroxy-3- t -butoxycarbonylaminopropanoyl] -10-deacetyl- 11,12-dihydrobaccatinu III (1b, R = Ph, R 2 = tBuO, R 3 = OH, R 4 = H), 13 - [(2R, 3S) -3-phenyl-2-hydroxy-3-f -butoxykarbonylaminopropanoyl] -C-seco-10-deacetylbaccatine III (5a, R = Ph, R2 = tBuO) and 13 - [(2R, 3S) -3-isobutyl-2-hydroxy-3-caproylamino-propanoyl] -C seco-10-deacetylbaccatin (5a, R 1 = isobutyl, R 2 = pentyl).
Tabulka 1: ICS0 taxanů 1a (R1 = Ph, R2= tBuO, R3= H, R4= OH),Table 1: IC S0 taxanes 1a (R1 = Ph, R2 = tBuO, R 3 = H, R 4 = OH)
1b (R1 = Ph, R2= tBuO, R3= OH, R4= H), a taxolu, měřeno u 6 buněčných linií1b (R1 = Ph, R2 = tBuO, R 3 = OH, R 4 = H), and taxol, measured at six cell lines
Standardní podmínky: substrát RPMI 1640 + 20 mM HEPES + 2 mMStandard conditions: RPMI substrate 1640 + 20 mM HEPES + 2 mM
L-glutaminL-glutamine
- 12 Tabulka 1: IC50 taxanů 5a (R, = Ph, R2= tBuO),- 12 Table 1: IC50 of taxanes 5a (R = Ph, R2 = tBuO)
5b (R1 = isobutyl, R2= pentyl), a taxolu, měřeno u 6 buněčných linií5b (R1 = isobutyl, R2 = pentyl), and taxol, measured at six cell lines
Standardní podmínky: substrát RPMI 1640 + 20 mM HEPES + 2 mM L-glutaminStandard conditions: substrate RPMI 1640 + 20 mM HEPES + 2 mM L-glutamine
Sloučeniny s různými substituenty v řetězci isoserinu se chovají podobně. Sloučeniny vykazují překvapivé výhody ve srovnání s taxolem v působení na buněčné linie, odolné vůči jiným protinádorové působícím látkám, jako je adriamycin a cis-platina. Rozdíly mezi taxolem a těmito produkty jsou ještě zřejmější u modelů in vivo, jako jsou athymické nahé myši s implantovaným lidským tumorem. Dále bylo zjištěno, že sloučeniny podle vynálezu, u nichž R2 je alkylová nebo alkenylová skupina, překvapivě na rozdíl od taxolu a jeho známých derivátů postrádají kardiotoxické účinky a mohou být tedy výhodně použity u kardiopatických pacientů, které nelze léčit taxolem a jeho známými deriváty.Compounds with different substituents in the isoserine chain behave similarly. The compounds show surprising advantages over taxol in the treatment of cell lines resistant to other antitumor agents, such as adriamycin and cisplatin. The differences between taxol and these products are even more evident in in vivo models, such as athymic nude mice implanted with a human tumor. Furthermore, it has been found that compounds of the invention in which R 2 is an alkyl or alkenyl group surprisingly, unlike taxol and its known derivatives, lack cardiotoxic effects and can therefore advantageously be used in cardiopathic patients who cannot be treated with taxol and its known derivatives.
- 13 Sloučeniny podle vynálezu se hodí pro začlenění do vhodných farmaceutických prostředků pro parenterální a perorální podávání. Pro intravenosní podávání se hlavně používají směsi polyethoxylovaného ricínového oleje a ethanolu, nebo liposomální přípravky, připravené s přírodním fosfatidylcholinem, či směsi přírodních fosfolipidů v přítomnosti cholesterolu.The compounds of the invention are suitable for incorporation into suitable pharmaceutical compositions for parenteral and oral administration. For intravenous administration, mixtures of polyethoxylated castor oil and ethanol, or liposomal formulations prepared with natural phosphatidylcholine, or mixtures of natural phospholipids in the presence of cholesterol are mainly used.
Níže uvedené příklady dále dokreslují vynález.The examples below further illustrate the invention.
Příklady provedení vynálezuDETAILED DESCRIPTION OF THE INVENTION
Příklad 1Example 1
Příprava 10-dehydro-10-deacetylbaccatinu III (4) g 10-deacetylbaccatinu III (3) bylo suspendováno v 350 ml methanolu, do něhož bylo přidáno 65 g Cu(OAc)2. Suspenze byla nepřetržitě míchána 120 hodin při laboratorní teplotě. Sole byly odfiltrovány a roztok byl chromatografován na 100 g silikagelu za eluce směsí hexanu a ethylacetátu (6:4). Krystalisací z ligroinu bylo získánoPreparation of 10-dehydro-10-deacetylbaccatin III (4) g of 10-deacetylbaccatin III (3) was suspended in 350 ml of methanol to which 65 g of Cu (OAc) 2 was added. The suspension was stirred continuously for 120 hours at room temperature. The salts were filtered off and the solution was chromatographed on 100 g of silica gel eluting with hexane / ethyl acetate (6: 4). Crystallization from ligroin was obtained
9,5 g látky (4), M+ při m/z 542.9.5 g of (4), M + at m / z 542.
Příklad 2Example 2
Příprava 10-deacetyl-10-epibaccatinu III (2a, R3=H, R4=RS=OH) a C-seko-10-deacetylbaccatinu III (5)Preparation of 10-deacetyl-10-epibaccatinu III (2a, R3 = H, R 4 = R S = OH) and C-seco-10-deacetylbaccatine III (5)
Roztok 300 mg látky (4) v 5 ml methanolu byl doplněn jedním ekvivalentem CeCI3. 3H2O, míchán 5 minut při laboratorní teplotě a poté doplněn 80 mg NaBH4. Roztok byl ovlivněn roztokem NH4CI, extrahován ethylacetátem a chromatografován na silikagelu za eluce směsí hexanuA solution of 300 mg of (4) in 5 mL of methanol was supplemented with one equivalent of CeCl 3 . 3H 2 O, stirred for 5 minutes at room temperature and then supplemented with 80 mg of NaBH 4 . The solution was treated with NH 4 Cl solution, extracted with ethyl acetate and chromatographed on silica gel eluting with hexane
- 14 a ethylacetátu (3:7). Získáno bylo 98 mg látky (2a) (M+ při m/z 544) a 120 mg látky (5) (M+ při m/z 546).14 and ethyl acetate (3: 7). 98 mg of (2a) (M + at m / z 544) and 120 mg of (5) (M + at m / z 546) were obtained.
10-deacetyl-10-epibaccatin III měl následující 1H-NMR spektrum (CDCI3): H2, d 5,68 J 6,8; H3, d 4,26 J 6,8; H5, d 5,03 J 7,1; H7/13, m 4,76; H10, br s 5,20; 10 OH, br s 3,44; H 16, s 1,14; H17, s 1,68; H18, s 2,22; H19, s 1,13; H20a, d 4,33; H20b, d 4,18; Ac, s 2,31; Bnz, br8,12 J8, br t 7,60 J 8, br t 17,49 J 8.10-Deacetyl-10-epibaccatin III had the following 1 H-NMR spectrum (CDCl 3 ): H 2, d 5.68 J 6.8; H3, d 4.26 J 6.8; H5, d 5.03 J 7.1; H7 / 13, m 4.76; H10, br s 5.20; 10 OH, br s 3.44; H 16, s 1.14; H17, s 1.68; H18, s 2.22; H19, s 1.13; H2O, d 4.33; H2 O, d 4.18; Ac, s 2.31; Bnz, br8.12 J8, br t 7.60 J 8, br t 17.49 J 8.
Příklad 3Example 3
Příprava 10-deacetyl-13-dehydrobaccatinu III (6)Preparation of 10-deacetyl-13-dehydrobaccatin III (6)
K suspenzi 1 g 10-deacetylbaccatinu III (3) ve 100 ml CH2CI2 byly přidány 3 g kyseliny meta-chlorperbenzoové a 1 g acetátu sodného. Suspenze byla nepřetržitě míchána 120 hodin při laboratorní teplotě a pak byla naředěna 5% vodným roztokem uhličitanu sodného. Organická fáze byla promyta 5% vodným roztokem uhličitanu sodného a vysušena do sucha. Zbytek byl vyčištěn na silikagelu za eluce směsí hexanu a ethylacetátu (3:7). Získáno bylo 789 mg látky (6), M+ při m/z 542.To a suspension of 1 g of 10-deacetylbaccatin III (3) in 100 ml of CH 2 Cl 2 was added 3 g of meta-chloroperbenzoic acid and 1 g of sodium acetate. The suspension was stirred continuously for 120 hours at room temperature and then diluted with 5% aqueous sodium carbonate solution. The organic phase was washed with 5% aqueous sodium carbonate solution and dried to dryness. The residue was purified on silica gel eluting with hexane / ethyl acetate (3: 7). 789 mg of (6), M + at m / z 542 was obtained.
Příklad 4Example 4
Příprava 10-deacetyl-11,12-dihydro-7-triethylsilyl-baccatinu III (2b, R3 = OH, R4 = H, Rs - O-TES)Preparation of 10-deacetyl-11,12-dihydro-7-triethylsilyl-baccatine III (2b, R 3 = OH, R 4 = H, R - O-TES)
1,6 g látky (6) bylo rozpuštěno v methylenchloridu a doplněno 370 mg 4-dimethylaminopyridinu a 2,5 ml triethylsilylchloridu. Po 2 hodinách při laboratorní teplotě byla reakční směs naředěna methylenchloridem a promyta vodou. Organická fáze byla zahuštěna do sucha. Získalo se tak 1,72 g zbytku, který byl spojen se 150 ml 95% ethanolu a ovlivněn působením 9 g NaBH4. Po 3 hodinách byla směs naředěna roztokem1.6 g of (6) was dissolved in methylene chloride and supplemented with 370 mg of 4-dimethylaminopyridine and 2.5 ml of triethylsilyl chloride. After 2 hours at room temperature, the reaction mixture was diluted with methylene chloride and washed with water. The organic phase was concentrated to dryness. This gave 1.72 g of residue which was combined with 150 ml 95% ethanol and influenced with 9 g of NaBH fourth After 3 hours, the mixture was diluted with solution
- 15 NH4CI a produkt byl extrahován ethylacetátem. Následnou chromatografii na silikagelu za použití směsi hexanu a ethylacetátu (7:3) bylo získáno 800 g látky (2b) (R3 = OH, R4 = H, Rs = O-TES).- 15 NH 4 Cl and the product was extracted with ethyl acetate. Subsequent chromatography on silica gel using hexane-ethyl acetate (7: 3) to afford 800 g of compound (2b) (R 3 = OH, R 4 = H, R = O-TES).
Příklad 5Example 5
Příprava 11,12-dihydro-7-TES-baccatinu III (2b, R3 = OH, R4 = H,Preparation of 11,12-dihydro-7-TES-baccatin III (2b, R 3 = OH, R 4 = H,
Rs = O-TES) a 11,12-dihydrobaccatinu III (2b, R3 = OH, R4 = H, Rs = O-TES)R s = O-TES) and 11,12-dihydrobaccatin III (2b, R 3 = OH, R 4 = H, R s = O-TES)
500 mg 10-deacetyl-11,12-dihydro-7-triethylsilylbaccatinu III (2b, R3 = OH, R4 = H, Rs = O-TES) bylo ponecháno reagovat v bezvodém pyridinu se 3 ekvivalenty acetylchloridu po dobu 6 hodin při teplotě 0°C. Reakční směs byla zředěna vodou a extrahována methylenchloridem. Po odpaření rozpouštědla byl zbytek krystalizován ze směsi acetonu a hexanu. Získalo se tak 510 mg 11,12-dihydro-7-TES-baccatinu III, M+ při m/z 702 III. Produkt byl rozpuštěn v methanolu a upravován zředěnou HCl až do úplné desilylace. Reakční směs byla zředěna vodou, extrahována ethylacetátem a krystalizována z vodného methanolu. Získalo se tak 400 mg 11,12-dihydrobaccatinu III, M+ při m/z 588.500 mg of 10-deacetyl-11,12-dihydro-7-triethylsilyl baccatin III (2b, R 3 = OH, R 4 = H, R = O-TES) are reacted in anhydrous pyridine with 3 equivalents of acetyl chloride for 6 hours at 0 ° C. The reaction mixture was diluted with water and extracted with methylene chloride. After evaporation of the solvent, the residue was crystallized from acetone / hexane. This gave 510 mg of 11,12-dihydro-7-TES-baccatin III, M + at m / z 702 III. The product was dissolved in methanol and treated with dilute HCl until complete desilylation. The reaction mixture was diluted with water, extracted with ethyl acetate and crystallized from aqueous methanol. This gave 400 mg of 11,12-dihydrobaccatin III, M + at m / z 588.
Příklad 6Example 6
Příprava 13-[(2R, 2S)-3-fenyl-2-hydroxy-3-ř-butoxykarbonylaminopropanoyl]-11,12-dihydrobaccatinu III (1b, R1 = Ph, R2 = t-BuO, R3 = OAc, R4 = H)Preparation of 13 - [(2R, 2S) -3-phenyl-2-hydroxy-3- t -butoxycarbonylaminopropanoyl] -11,12-dihydrobaccatin III (1b, R 1 = Ph, R 2 = t-BuO, R 3 = OAc) , R 4 = H)
500 mg 11,12-dihydrobaccatinu III (2b, R3 = OAc, R4 = H, Rs = O-TES) bylo rozpouštěno ve 20 ml toluenu spolu s 0,45 g (4S, 5R) - N -ř-butoxykarbonyl-2,2-dimethylfenyl-5-oxazolydinkarboxylové kyseliny, dicyklohexylkarbodiimidem (1,03 ekviv.) a N,N-dimethylamido- 16 pyridinem (0,2 ekviv.) 2 hodiny při 80°C. Reakční směs byla promývána vodou až do odstranění přebytku reagencií a poté zahuštěna do sucha. Zbytek byl upraven působením methanolu, obsahujícího 1% kyselinu mravenčí, po dobu 4 hodin při laboratorní teplotě. Methanolový roztok byl naředěn vodou, neutralizován a extrahován ethylacetátem. Organická fáze byla zahuštěna do sucha a zbytek byl upraven roztokem, obsahujícím 1,5 ekvivalentu uhličitanu di-ř-butylnatého a kyselého uhličitanu sodného (sody bikarbony) v 15 ml tetrahydrofuranu. Reakční směs byla naředěna vodou, extrahována ethylacetátem a heteroacetátová fáze byla zahuštěna do sucha. Zbytek byl k dokončení desilylace rozpuštěn v methanolu, okyseleném kyselinou chlorovodíkovou. Pak byl roztok naředěn vodou a extrahován ethylacetátem. Zbytek, získaný odpařením fáze heteroacetátu, byl chromatografován na silikagelu za eluce směsí acetonu a hexanu (1:1) k odstranění reakčních nečistot. Získalo se tak 580 mg produktu o M+ při m/z 851.500 mg of 11,12-dihydrobaccatinu III (2b, R 3 = OAc, R 4 = H, R = O-TES) was dissolved in 20 ml of toluene together with 0.45 g of (4S, 5R) - N -R- butoxycarbonyl-2,2-dimethylphenyl-5-oxazolydinecarboxylic acid, dicyclohexylcarbodiimide (1.03 equiv) and N, N-dimethylamido-16-pyridine (0.2 equiv) at 80 ° C for 2 h. The reaction mixture was washed with water until excess reagent was removed and then concentrated to dryness. The residue was treated with methanol containing 1% formic acid for 4 hours at room temperature. The methanol solution was diluted with water, neutralized and extracted with ethyl acetate. The organic phase was concentrated to dryness and the residue treated with a solution containing 1.5 equivalents of di-t-butyl carbonate and sodium bicarbonate in 15 ml of tetrahydrofuran. The reaction mixture was diluted with water, extracted with ethyl acetate, and the heteroacetate phase was concentrated to dryness. The residue was dissolved in methanol acidified with hydrochloric acid to complete desilylation. The solution was then diluted with water and extracted with ethyl acetate. The residue obtained by evaporation of the heteroacetate phase was chromatographed on silica gel eluting with acetone / hexane (1: 1) to remove reaction impurities. 580 mg of product with M + at m / z 851 were obtained.
Příklad 7Example 7
Příprava 13-[(2R, 2S)-3-benzoylamino-3-fenyl-2-hydroxypropanoylj-11,12-dihydrobaccatinu III (1b, R1 = R2 = Ph, R3 = OAc, R4 = H)Preparation of 13 - [(2R, 2S) -3-Benzoylamino-3-phenyl-2-hydroxypropanoyl] -11,12-dihydrobaccatin III (1b, R 1 = R 2 = Ph, R 3 = OAc, R 4 = H)
500 mg 11,12-dihydro-7-TES-baccatinu III (2b, R3 = OAc, R4 = H, Rs = O-TES) bylo rozpouštěno ve 20 ml toluenu spolu s 1,5 g (4S, 5R)-N-benzoyl-2,2-dímethyl-4-fenyl-5-oxazolydinkarboxylové kyseliny, s dicyklohexylkarbodiimidem (1,03 ekviv.) a N,N-dimethylamidopyridínem (0,2 ekviv.) 2 hodiny při 80°C. Reakční směs byla promývána vodou až do odstranění přebytku reagujících látek a poté zahuštěna do sucha. Zbytek byl upraven působením methanolu, obsahujícího 1% kyselinu mravenčí, po 4 hodiny při laboratorní teplotě. Methanolový roztok byl naředěn vodou, neutralizován a extrahován ethylacetátem.500 mg of 11,12-dihydro-7-TES-baccatine III (2b, R 3 = OAc, R 4 = H, R = O-TES) was dissolved in 20 ml of toluene together with 1.5 g of (4S, 5R 1-N-Benzoyl-2,2-dimethyl-4-phenyl-5-oxazolydinecarboxylic acid, with dicyclohexylcarbodiimide (1.03 equiv) and N, N-dimethylamidopyridine (0.2 equiv) at 80 ° C for 2 h. The reaction mixture was washed with water until excess reagents were removed and then concentrated to dryness. The residue was treated with methanol containing 1% formic acid for 4 hours at room temperature. The methanol solution was diluted with water, neutralized and extracted with ethyl acetate.
- 17 Organická fáze byla zahuštěna do sucha a zbytek byl spojen s methanolem, okyseleným kyselinou chlorovodíkovou, k dokončení desilylace. Poté byl roztok naředěn vodou a extrahován ethylacetátem. Zbytek získaný odpařením a fáze heteroacetátu byly chromatografovány na silikagelu za eluce směsí acetonu a hexanu (1:1) k odstranění reakčních nečistot. Získalo se tak 530 mg produktu, M+ při m/z 855.The organic phase was concentrated to dryness and the residue was combined with methanol, acidified with hydrochloric acid, to complete desilylation. The solution was then diluted with water and extracted with ethyl acetate. The evaporation residue and the heteroacetate phase were chromatographed on silica gel eluting with acetone / hexane (1: 1) to remove the reaction impurities. 530 mg of product are obtained, M + at m / z 855.
Příklad 8Example 8
Příprava 13-[(2R, 2S)-3-fenyl-2-hydroxy-3-ř-butoxykarbonyiaminopropanoyl]-10-epi-10-deacetylbaccatinu III (1a, R, = Ph, R2 = t-BuO, R3 = H, R4 = OH)Preparation of 13 - [(2R, 2S) -3-phenyl-2-hydroxy-3- t -butoxycarbonylamino-propanoyl] -10-epi-10-deacetylbaccatin III (1a, R 1 = Ph, R 2 = t-BuO, R 3 = H, R 4 = OH)
500 mg 10-deacetyl-10-epibaccatinu III (2a, R3 =H, R4 = Rs = OH) bylo rozpuštěno v 15 ml bezvodého pyridinu, upraveno působením 3 ekvivalentů trichlorethoxykarbonylchloridu (TROC-CI) po dobu 5 minut při 80°C a poté ochlazeno na laboratorní teplotu. K rozpadu nadbytku látky TROC-CI byl přidán 1 ml methanolu. Roztok byl naředěn ledovou vodou a extrahován chloroformem za promyti organické fáze zředěným roztokem kyseliny chlorovodíkové. Organická fáze byla odpařena do sucha a na zbytek bylo při laboratorní teplotě působeno 24 hodin roztokem toluenu, obsahujícího 3 ekvivalenty (4S,5R)-N-t-butoxykarbonyl-2,2-di-methyl-4-fenyl-5-oxazolidinkarboxylové kyseliny, 3 ekvivalenty dicyklohexylkarbodiimidu a 0,2 ekvivalentu Ν,Ν-dimethylaminopyridinu. Reakční směs byia promyta vodou a organická fáze byla ve vakuu odpařena do sucha. Zbytek byl převeden do methanolu a upraven působením 1 ekvivalentu kyseliny p-toluensulfonové kyseliny po dobu 48 hodin, poté byl naředěn vodou a extrahován ethylacetátem. Organická fáze byla odpařena ve vakuu, zbytek byl převeden do 200 ml směsi kyseliny octové a ethylacetátu (1:1) a 3 hodiny byl vystaven působení 11 ekvivalentů práškového zinku při teplotě 30°C. Pevný materiál byl odfiltrován a roztok byl naředěn500 mg of 10-deacetyl-10-epibaccatinu III (2a, R3 = H, R 4 = R s = OH) was dissolved in 15 ml of anhydrous pyridine, treated with at three equivalents of trichloroethoxycarbonyl chloride (TROC-Cl) for 5 minutes at 80 ° C and then cooled to room temperature. 1 ml of methanol was added to decompose excess TROC-CI. The solution was diluted with ice water and extracted with chloroform, washing the organic phase with dilute hydrochloric acid solution. The organic phase was evaporated to dryness and the residue was treated with a toluene solution containing 3 equivalents of (4S, 5R) -Nt-butoxycarbonyl-2,2-dimethyl-4-phenyl-5-oxazolidinecarboxylic acid at room temperature for 24 hours. equivalents of dicyclohexylcarbodiimide and 0.2 equivalents of Ν, Ν-dimethylaminopyridine. The reaction mixture was washed with water and the organic phase was evaporated to dryness in vacuo. The residue was taken up in methanol and treated with 1 equivalent of p-toluenesulfonic acid for 48 hours, then diluted with water and extracted with ethyl acetate. The organic phase was evaporated in vacuo, the residue was taken up in 200 ml of a 1: 1 mixture of acetic acid and ethyl acetate and treated with 11 equivalents of zinc powder at 30 ° C for 3 hours. The solid material was filtered off and the solution was diluted
- 18 vodou, extrahován ethylacetátem a chromatografován na silikagelu za eluce směsí ethylacetátu a hexanu (1:4). Získalo se tak 512 mg produktu (1a), M+ při m/z 807.- 18 water, extracted with ethyl acetate and chromatographed on silica gel eluting with ethyl acetate / hexane (1: 4). 512 mg of product (1a), M + at m / z 807, were obtained.
Příklad 9Example 9
Příprava 7,9-di-triethylsilyl-C-seko-10-deacetylbaccatinu IIIPreparation of 7,9-di-triethylsilyl-C-seco-10-deacetylbaccatin III
Roztok látky (5) (200 mg, 0,37 mmol) v bezvodém dimethylformamidu (DMF, 5 ml) byl přidán k imidazolu (75 mg, 1,11 mmol, 3 ekv. mol.) a triethylsilylchloridu (TES, 186 ml, 167,3 mg, 1,11 mmol, 3 ekv. mol.) a reakční směs byla míchána 10 minut při laboratorní teplotě. Reakce byla ověřována pomocí tenkovrstevné chromatografie (TLC) ve směsi hexanu a ethylacetátu (3:7), Rf výchozí látky bylo 0,10; Rf produktu 0,80. Reakce pak byla zastavena přídavkem vody a Celitu®, a sraženina byla zfiltrována a promyta vodou k odstranění DMF a poté CHCI3 k vydělení produktu. Po vyčištění kolonovou chromatografii (za použití směsi hexanu a ethylacetátu 9:1 k eluci silanolu a poté směsi hexanu a ethylacetátu 6:4 k eluci produktu) bylo získáno 146 mg v nadpisu uvedeného produktu (51%).A solution of (5) (200 mg, 0.37 mmol) in anhydrous dimethylformamide (DMF, 5 mL) was added to imidazole (75 mg, 1.11 mmol, 3 eq.) And triethylsilyl chloride (TES, 186 mL, 167.3 mg, 1.11 mmol, 3 eq) and the reaction mixture was stirred at room temperature for 10 minutes. The reaction was checked by thin layer chromatography (TLC) in a mixture of hexane and ethyl acetate (3: 7), R f starting material was 0.10; Product R f 0.80. The reaction was then quenched by the addition of water and Celite®, and the precipitate was filtered and washed with water to remove DMF and then CHCl 3 to separate the product. Purification by column chromatography (eluting with hexane: ethyl acetate 9: 1 to elute silanol followed by hexane: ethyl acetate 6: 4 to elute the product) gave 146 mg of the title product (51%).
Příklad 10Example 10
Příprava 13-[(2R, 3S)-3-fenyl-2-hydroxy-3-f-butoxykarbonylaminopropanoyl]-C-seko-10-deacetylbaccatinu III (5a, R,= Ph, R2=ř-BuO)Preparation of 13 - [(2R, 3S) -3-phenyl-2-hydroxy-3- t -butoxycarbonylaminopropanoyl] -C-seco-10-deacetylbaccatin III (5a, R 1 = Ph, R 2 = t-BuO)
Roztok produktu, získaného v Příkladu 9 (126 mg, 0,16 mmol) v bezvodém toluenu (5 ml), byl doplněn 67,5 mg dicyklohexylkarbodlimidu (0,327 mmol, 2 mol. ekv.), 105 mg (4S, 5R)-N-Boc-2-(2,4-dimethoxyfenyl)-4-fenyl-5-oxazolldinkarboxylové kyseliny (0,327 mmol, 2 mol. ekv.) a 5 mg 4-dimethylaminopyridinu. Směs byla zahřívána 24 hodin na 60°C a zředěna nasyceným vodným roztokem NaHCO3 a ethylacetátu.A solution of the product obtained in Example 9 (126 mg, 0.16 mmol) in anhydrous toluene (5 mL) was charged with 67.5 mg of dicyclohexylcarbodimide (0.327 mmol, 2 mol equiv.), 105 mg (4S, 5R) - N-Boc-2- (2,4-dimethoxyphenyl) -4-phenyl-5-oxazolinedinecarboxylic acid (0.327 mmol, 2 mol eq) and 5 mg of 4-dimethylaminopyridine. The mixture was heated at 60 ° C for 24 h and diluted with saturated aqueous NaHCO 3 and ethyl acetate.
- 19 Zbytek byl vyčištěn kolonovou chromatografii (hexan/ethyiacetát, 8:2) za vzniku 175 mg 13-esteru (95 %). Zbytek byl převeden do 50 mi směsi methanol/HCI (0,01%) a reakční směs byla ponechána 1 hodinu při laboratorní teplotě. Roztok byl alkalizován na pH 5 a ve vakuu zahuštěn do sucha. Vzniklý zbytek byl chromatografován na koloně siiikagelu za eluce směsí methylenchloridu a methanolu (98:2). Po krystalizaci z ethylacetátu bylo získáno 85 mg v nadpisu uvedené sloučeniny.The residue was purified by column chromatography (hexane / ethyl acetate, 8: 2) to give 175 mg of the 13-ester (95%). The residue was taken up in 50 mL of methanol / HCl (0.01%) and the reaction mixture was left at room temperature for 1 hour. The solution was basified to pH 5 and concentrated to dryness in vacuo. The resulting residue was chromatographed on a silica gel column eluting with a mixture of methylene chloride and methanol (98: 2). Crystallization from ethyl acetate gave 85 mg of the title compound.
Příklad 11Example 11
Příprava 13-[(2R, 2S)-3-isobutyl-2-hydroxy-3-kaproylaminopropanoyl]-C-seko-10-deacetylbaccatinu III (5a, R1 = Ph, R2 = pentyl)Preparation of 13 - [(2R, 2S) -3-isobutyl-2-hydroxy-3-caproylaminopropanoyl] -C-seco-10-deacetylbaccatin III (5a, R 1 = Ph, R 2 = pentyl)
Roztok produktu, získaného v Příkladu 9 (126 mg, 0,16 mmol), v bezvodém toluenu (5 ml) byl přidán k 67,5 mg dicyklohexylkarbodiimidu (0,327 mmol, 2 mol. ekv.), 140 mg kyseliny (4S, 5R)-N-kaproyl-2-(2,4dimethoxyfenyl)-4-isobutyl-5-oxazolidinkarboxylové (0,327 mmol, 2 mol. ekv.) a 5 mg 4-dimethylaminopyridinu. Směs byla zahřívána 24 hodin na 60°C a zředěna nasyceným vodným roztokem NaHCO3 a ethylacetátu. Vzniklý zbytek byl vyčištěn kolonovou chromatografii (hexan/ethylacetát, 8:2) za vzniku 175 mg 13-esteru (95 %). Zbytek byl převeden do 50 ml směsi methanol/HCI (0,01%) a reakční směs byla ponechána 1 hodinu při laboratorní teplotě. Roztok byl alkalizován na pH 5 a ve vakuu zahuštěn do sucha. Vzniklý zbytek byl chromatografován na koloně siiikagelu za eluce směsí methylenchloridu a methanolu (98:2). Po krystalizaci z ethylacetátu bylo získáno 88 mg v nadpisu uvedené sloučeniny.A solution of the product obtained in Example 9 (126 mg, 0.16 mmol) in anhydrous toluene (5 mL) was added to 67.5 mg of dicyclohexylcarbodiimide (0.327 mmol, 2 mol equiv.), 140 mg of acid (4S, 5R). 1-N-Caproyl-2- (2,4-dimethoxyphenyl) -4-isobutyl-5-oxazolidinecarboxylic acid (0.327 mmol, 2 mol eq) and 5 mg of 4-dimethylaminopyridine. The mixture was heated at 60 ° C for 24 h and diluted with saturated aqueous NaHCO 3 and ethyl acetate. The resulting residue was purified by column chromatography (hexane / ethyl acetate, 8: 2) to give 175 mg of the 13-ester (95%). The residue was taken up in 50 mL of methanol / HCl (0.01%) and the reaction mixture was left at room temperature for 1 hour. The solution was basified to pH 5 and concentrated to dryness in vacuo. The resulting residue was chromatographed on a silica gel column eluting with methylene chloride / methanol (98: 2). Crystallization from ethyl acetate yielded 88 mg of the title compound.
Zastupuje:Represented by:
Mq - qg.Mq - qg.
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| US6395770B1 (en) * | 1995-10-26 | 2002-05-28 | Baker Norton Pharmaceuticals, Inc. | Method and compositions for administering taxanes orally to human patients |
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| EP0868422A1 (en) * | 1996-09-24 | 1998-10-07 | Marigen S.A. | Ultramicroemulsion of spontaneously dispersible concentrates of esters of baccatin-iii compounds with antitumor and antiviral effect |
| US5773464A (en) * | 1996-09-30 | 1998-06-30 | Bristol-Myers Squibb Company | C-10 epoxy taxanes |
| US5977386A (en) * | 1996-12-24 | 1999-11-02 | Bristol-Myers Squibb Company | 6-thio-substituted paclitaxels |
| US5902822A (en) * | 1997-02-28 | 1999-05-11 | Bristol-Myers Squibb Company | 7-methylthiooxomethyl and 7-methylthiodioxomethyl paclitaxels |
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| BR9809694A (en) * | 1997-05-27 | 2000-10-03 | Baker Norton Pharma | Process and composition for administering taxanes orally to human patients |
| IT1308636B1 (en) * | 1999-03-02 | 2002-01-09 | Indena Spa | PROCEDURE FOR THE PREPARATION OF TASSANI FROM 10-DESACETILBACCATINAIII. |
| AU775373B2 (en) | 1999-10-01 | 2004-07-29 | Immunogen, Inc. | Compositions and methods for treating cancer using immunoconjugates and chemotherapeutic agents |
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| US6649632B2 (en) | 2000-02-02 | 2003-11-18 | Fsu Research Foundation, Inc. | C10 ester substituted taxanes |
| EP1129991A1 (en) * | 2000-03-02 | 2001-09-05 | Degussa AG | Process for the preparation of a titanium-containing zeolite |
| US7064980B2 (en) * | 2003-09-17 | 2006-06-20 | Sandisk Corporation | Non-volatile memory and method with bit line coupled compensation |
| HN2005000054A (en) * | 2004-02-13 | 2009-02-18 | Florida State University Foundation Inc | REPLACED TAXANS WITH CYCLOPENTILO ESTERS IN C10 |
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| EP2183234A4 (en) * | 2007-08-22 | 2012-02-29 | Canada Inc 6570763 | Process for converting 9-dihydro-13-acetylbaccatin iii into docetaxel or paclitaxel |
| EP2276755A4 (en) * | 2008-03-31 | 2011-05-04 | Univ Florida State Res Found | C(10) ethyl ester and c(10) cyclopropyl ester substituted taxanes |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5175315A (en) * | 1989-05-31 | 1992-12-29 | Florida State University | Method for preparation of taxol using β-lactam |
| KR930702323A (en) * | 1991-07-17 | 1993-09-08 | 하지메 나까가와 | Compound having antitumor activity (NSC-LSC1) and preparation method thereof |
| US5399726A (en) * | 1993-01-29 | 1995-03-21 | Florida State University | Process for the preparation of baccatin III analogs bearing new C2 and C4 functional groups |
| FR2688499B1 (en) * | 1992-03-10 | 1994-05-06 | Rhone Poulenc Rorer Sa | PROCESS FOR THE PREPARATION OF BETA-PHENYLISOSERINE AND ITS ANALOGS. |
| US5200534A (en) * | 1992-03-13 | 1993-04-06 | University Of Florida | Process for the preparation of taxol and 10-deacetyltaxol |
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1995
- 1995-07-21 DK DK95927699T patent/DK0773938T3/en active
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- 1995-07-21 DE DE69507702T patent/DE69507702T2/en not_active Expired - Lifetime
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- 1995-07-21 AU AU31641/95A patent/AU684218B2/en not_active Ceased
- 1995-07-21 AT AT95927699T patent/ATE176464T1/en active
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- 1995-07-21 EP EP95927699A patent/EP0773938B1/en not_active Expired - Lifetime
- 1995-07-21 SK SK100-97A patent/SK281526B6/en not_active IP Right Cessation
- 1995-07-24 US US08/505,924 patent/US5756776A/en not_active Expired - Lifetime
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1997
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1998
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1999
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2000
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PD00 | Pending as of 2000-06-30 in czech republic | ||
| MM4A | Patent lapsed due to non-payment of fee |
Effective date: 20120721 |